Oledetrim® d3 forte

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT OLIDETRIM® D3 FORTE (OLIDETRIM D3 FORTE)

Composition:

Active substance: cholecalciferol;

1 soft capsule contains 0.25 mg cholecalciferol, equivalent to 10,000 IU vitamin D3;

Excipients: capsule contents: purified safflower oil; capsule shell: gelatin, glycerol, purified water, medium-chain triglycerides (traces).

Pharmaceutical form. Soft capsules.

Main physicochemical properties: light yellow, oval, soft capsules with a central seam line, filled with a light yellow liquid.

Pharmacotherapeutic group. Vitamins. Vitamin D and analogues. Cholecalciferol.

ATC code A11C C05.

Pharmacological Properties

Pharmacodynamics

Cholecalciferol (vitamin D3) is synthesized in the skin under the influence of ultraviolet radiation, including sunlight. In its biologically active form, vitamin D3 stimulates calcium absorption in the intestine, calcium penetration into osteoid, and calcium release from bone tissue. In the small intestine, it promotes both rapid and delayed calcium uptake. In addition, passive and active phosphate transport is enhanced. In the kidneys, it reduces calcium and phosphate excretion by stimulating tubular reabsorption. The biologically active form of cholecalciferol directly suppresses parathyroid hormone production in the parathyroid glands. Parathyroid hormone secretion is further inhibited due to increased intestinal calcium absorption induced by biologically active vitamin D3.

Pharmacokinetics

Absorption

Vitamin D, in the amounts present in food, is almost completely absorbed from the diet. It is absorbed together with dietary lipids and bile acids; therefore, administration of vitamin D during the main meal of the day may enhance its absorption.

Distribution

Cholecalciferol accumulates in adipocytes, and its biological half-life is approximately 50 days.

After a single oral dose of cholecalciferol, the maximum serum concentration of 25(OH)D3—the main storage form—is reached after approximately 7 days.

Biotransformation

Metabolic conversion of cholecalciferol occurs in the liver via microsomal hydroxylase, forming 25-hydroxycholecalciferol (25(OH)D3). This is subsequently converted in the kidneys into 1,25-dihydroxycholecalciferol, which is the biologically active form. Circulating metabolites are bound to a specific α-globulin.

Elimination

25(OH)D3 is eliminated slowly, with an apparent half-life in serum of approximately 50 days. Cholecalciferol and its metabolites are excreted primarily via bile and feces. After administration of high doses of vitamin D, serum concentrations of 25-hydroxycholecalciferol may remain elevated for several months. Hypercalcemia caused by overdose may persist for several weeks (see section "Overdose").

Clinical characteristics.

Indications.

• Treatment of vitamin D deficiency and conditions associated with vitamin D deficiency in adults.

Vitamin D deficiency is defined as a 25-hydroxycholecalciferol (25(OH)D) level < 20 ng/mL (< 50 nmol/L); the target concentration for optimal vitamin D effect is defined as 30–50 ng/mL (75–125 nmol/L).

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients.
• Hypercalcaemia and/or hypercalciuria.
• Nephrolithiasis and/or nephrocalcinosis.
• Severe renal impairment.
• Hypervitaminosis D.
• Pseudohypoparathyroidism (vitamin D requirement may be lower than during normal vitamin sensitivity; risk of prolonged overdose).
• Sarcoidosis.
• Tuberculosis.
• Additional intake of vitamin D (may lead to overdose).
• Pediatric age (under 18 years).

Interaction with other medicinal products and other forms of interactions.

Concomitant use of anticonvulsants (e.g., phenytoin) or barbiturates (and possibly other enzyme-inducing drugs) may lead to reduced vitamin D3 efficacy due to metabolic inactivation.

When treating with thiazide diuretics, plasma calcium levels should be monitored due to reduced renal calcium excretion.

Glucocorticoids increase vitamin D metabolism, which may lead to reduced vitamin D efficacy.

Oral intake of vitamin D together with cardiac glycosides may enhance the efficacy and toxicity of digoxin due to increased calcium levels (risk of cardiac arrhythmias). In such patients, regular ECG monitoring and assessment of plasma and urinary calcium levels are required, as well as determination of digoxin or digitoxin concentration, if possible.

Concomitant administration of ion-exchange resins such as cholestyramine, colestipol hydrochloride, orlistat, or laxatives such as mineral oil, may reduce vitamin D absorption in the gastrointestinal tract.

The cytotoxic agent actinomycin and imidazole antifungal agents reduce vitamin D3 activity by inhibiting the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol by renal enzymes, resulting in reduced 25-hydroxyvitamin D-1-hydroxylase activity.

Rifampicin may reduce cholecalciferol efficacy due to induction of hepatic enzymes.

Isoniazid may reduce cholecalciferol efficacy by inhibiting the metabolic activation of cholecalciferol.

Concomitant use of benzothiadiazine derivatives (thiazide diuretics) increases the risk of hypercalcaemia due to reduced renal calcium excretion. Therefore, plasma calcium levels in blood and urine should be monitored.

Ketoconazole may reduce the biosynthesis and catabolism of 1,25(OH)2-cholecalciferol.

Concomitant use with medicinal products containing high doses of calcium and phosphorus increases the risk of hyperphosphataemia.

Vitamin D may antagonize medicinal products used in hypercalcaemia, such as calcitonin, etidronate, and pamidronate.

Concomitant use of cholecalciferol with antacids containing aluminum or magnesium may provoke aluminum toxicity to bone and hypermagnesaemia in patients with renal insufficiency.

The combination of cholecalciferol with metabolites or analogues of vitamin D should be avoided. Concomitant administration of vitamin D3 with metabolites or analogues of vitamin D is possible only exceptionally and only under monitoring of serum calcium levels, as this increases the risk of toxic effects.

Special precautions for use

The medicinal product should be used with special caution in patients with impaired renal function. In such patients, calcium and phosphate levels should be monitored.

There is no direct evidence of a causal relationship between vitamin D intake and kidney stone formation; however, this risk is quite possible, especially when calcium is co-administered.

Cholecalciferol is not recommended for individuals predisposed to developing calcium-containing kidney stones.

The medicinal product should be used with special caution in patients with impaired renal function who are receiving benzothiadiazine derivatives, as well as in immobilized patients (due to the risk of hypercalcemia and hypercalciuria). In such patients, calcium and phosphate levels should be monitored. The risk of soft tissue calcification should also be considered. In patients with severe renal insufficiency, normal metabolic conversion of cholecalciferol is impaired; therefore, other forms of vitamin D should be used (see section "Contraindications").

If treatment is prolonged and the daily dose of vitamin D exceeds 1000 IU, serum calcium levels should be monitored, and kidney function should be monitored by measuring serum creatinine. This monitoring is particularly important for elderly patients receiving concomitant therapy with cardiac glycosides or diuretics (see section "Interaction with other medicinal products and other forms of interaction"), as well as for patients at high risk of stone formation. In case of hypercalciuria (calcium level exceeding 300 mg [7.5 mmol]/24 hours) or signs of impaired renal function, the dose should be reduced or treatment discontinued.

To prevent hypercalcemia during treatment, medical supervision is required.

Caution is necessary when prescribing to patients undergoing treatment for cardiovascular diseases (see section "Interaction with other medicinal products and other forms of interaction").

Cholecalciferol should not be used in patients with sarcoidosis due to the risk of accelerated conversion of vitamin D into its active metabolites. In such patients, plasma and urinary calcium levels should be monitored.

Prior to initiating vitamin D therapy, a thorough clinical assessment of the patient should be performed by a physician, taking into account additional vitamin D intake from specific dietary sources, as well as the patient's sun exposure.

The need for additional calcium intake should be individually assessed for each patient. Any additional calcium intake should be strictly under medical supervision.

Elderly patients

Age > 65 years

In a recent study, elderly individuals with a history of falls showed an increased risk of falling when receiving monthly doses of 60,000 IU of vitamin D. Therefore, the use of cholecalciferol in elderly patients is recommended only after careful benefit-risk assessment and only when clearly indicated. The dose should not exceed 24,000 IU per month. For elderly patients with a history of falls, daily vitamin D supplementation should be considered.

Age > 70 years

When treating with vitamin D according to a protocol involving a loading dose, serum levels of 25(OH)D3 should be regularly monitored. Treatment should be discontinued if levels reach ≥ 50 ng/mL.

Use during pregnancy or breastfeeding

Pregnancy

Vitamin D intake during pregnancy is associated with a reduced risk of low birth weight for gestational age, as well as with accelerated neonatal growth without increasing the risk of intrauterine or neonatal death or congenital anomalies. Vitamin D intake during pregnancy at a dose of 2000 IU/day may reduce the risk of intrauterine and neonatal mortality.

During pregnancy, women should follow the recommendations of their treating physician, as vitamin D requirements may vary depending on disease severity and response to treatment.

The medicinal product should not be used during pregnancy except in cases where the woman's clinical condition requires cholecalciferol treatment at a dose necessary to correct vitamin D deficiency.

Breastfeeding

Vitamin D and its metabolites are excreted in breast milk. There have been no reported cases of overdose in breastfed infants. The recommended daily dose for breastfeeding women is 2000 IU. Breastfeeding women should not take high doses of vitamin D. Vitamin D supplementation in breastfeeding women is not recommended as an additional agent for the infant.

Fertility

No effects on reproductive function or fertility were observed in studies investigating the impact of cholecalciferol at therapeutic doses.

Ability to affect reaction speed when driving or operating machinery

Studies on the effect of the medicinal product on the ability to drive or operate machinery have not been conducted. Adverse effects of cholecalciferol that could impair the ability to drive or operate machinery are unknown.

Method of Administration and Dosage

Dosage

The dosage regimen and administration schedule should be individually selected depending on the clinical manifestations of each patient.

Treatment of vitamin D deficiency and conditions associated with vitamin D deficiency in adults

Treatment of vitamin D deficiency and related conditions should be carried out for 3 months or until achieving a 25(OH)D concentration of ≥ 30–50 ng/mL. Afterwards, continuous administration of a maintenance (preventive) dose, recommended for healthy individuals, is advised, taking into account the patient's age and body weight.

Adults with laboratory-confirmed vitamin D deficiency

For adults with laboratory-confirmed vitamin D deficiency, the dose is 10,000 IU/day for 1–3 months, followed by a maintenance dose of 2000 IU/day or 10,000 IU/week, depending on the patient's age and body weight. Treatment must be conducted under medical supervision. Obese adult patients (with BMI ≥ 30 kg/m²) may require a higher maintenance dose, such as 4000 IU/day, depending on the degree of obesity.

To ensure that the target 25(OH)D concentration has been achieved, measurement of the 25(OH)D level should be performed approximately 3–4 months after initiating maintenance therapy.

Patients with hepatic impairment

Dose adjustment is not required.

Patients with renal impairment

The medicinal product should not be administered to patients with severe renal impairment without medical monitoring of kidney function (see section "Contraindications").

OLIDETRIM® D3 Forte with other medicines, food and drinks

Other medicinal products, dietary supplements, food or drinks containing vitamin D (cholecalciferol), calcitriol, or other vitamin D metabolites and analogues should not be used without physician supervision.

Method of Administration

For oral use.

The capsule should be taken whole, with sufficient water, preferably during a main meal.

Children

OLIDETRIM® D3 Forte, 10,000 IU capsules, should not be used in children (under 18 years of age).

Overdose

Symptoms

Acute and chronic overdose of vitamin D3 may cause hypercalcemia and increased calcium concentration in blood plasma and urine. Symptoms may be non-specific and include nausea, vomiting, and diarrhea in the early stages, and constipation, anorexia, increased fatigue, headache, muscle and joint pain, muscle weakness, polydipsia, polyuria, kidney stone formation, nephrocalcinosis, renal failure, calcium deposition in tissues, ECG changes, arrhythmias, and pancreatitis. Isolated reports of fatal hypercalcemia have been reported.

Treatment

The primary measure is to discontinue vitamin D intake. Normalization of calcium levels following vitamin D intoxication-induced hypercalcemia may take several weeks.

Depending on the severity of hypercalcemia, a calcium-free or low-calcium diet may be used. Increased fluid intake is recommended, along with forced diuresis using furosemide, and administration of glucocorticoids and calcitonin.

Phosphate infusions should not be used to reduce hypercalcemia in vitamin D toxicity due to the risk of metastatic calcification.

Adverse reactions.

Frequency is defined as follows: uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); or frequency not known (cannot be estimated based on available data).

Single reports of fatal outcomes have been reported (see section "Overdose").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 30 °C. Keep in the original packaging to protect from light. Keep out of reach and sight of children.

Packaging.

15 capsules in a blister pack. 2, 4 or 6 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Pharmaceutical Works POLPHARMA S.A. / Pharmaceutical Works POLPHARMA S.A.

Manufacturer's address and location of operations.

Medana Branch in Sieradz, 10 Wladyslawa Lokietka Street, 98-200 Sieradz, Poland /
Medana Branch in Sieradz, 10, Wladyslawa Lokietka Str., 98-200 Sieradz, Poland